The purpose of the research outlined in the Research Scientist Award is to investigate the neurobiology of schizophrenia by integrating clinical, neurobehavioral, neuroanatomic and neurophysiologic measures of brain function. In the clinical domain, symptoms and functioning will be evaluated longitudinally. A lifespan perspective of schizophrenia, from new onset patients to the elderly, will enable examination of the disease process and establish a prospective brain collection for antemortem- postmortem correlations. Gender differences and vulnerability will be assessed from a neuropsychiatric perspective. The neurobehavioral measures will evaluate major cognitive and affective computational domains related to regional brain function. Neuroanatomic parameters will be obtained with magnetic resonance imaging (MRI) volumetric measurements and with postmortem neuropathologic studies. Neurophysiologic parameters will consist of cerebral blood flow (CBF) and glucose metabolism measured with positron emission tomography (PET) and neuroreceptor density and affinity will be measured with PET and with single-photon emission computed tomography (SPECT), as well as postmortem receptor autoradiography. It is proposed to further develop and apply magnetic resonance spectroscopy (MRS) to examine biochemical parameters and magnetic resonance flow (MRF) to evaluate CBF related changes. The integration will be achieved through the use of "neurobehavioral" and pharmacologic probes that permit testing hypotheses on brain behavior relation as a function of clinical profile.